6-fluoro-17alpha-hydroxypregnanes and esters



United States Patent 6-FLUORO-17a-HYDROXYPREGNAN ES AND ESTERS John C. Babcock, Portage Township, Kalamazoo County, and J Allan Campbell and John A. Hogg, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application February 19, 1958 Serial No. 716,002

10 Claims. (Cl. 260-397.4)

The present invention relates to steroid compounds and is more particularly concerned with the novel 6-fluoro- 17a-hydroxy-l-allopregnene-3,20-dione, 6-fl1101'0-17oz-hydroxy-l,4-pregnadiene-3,ZO-diones (both the 611- and 6B- fluoro isomers) and 17-esters thereof, and the novel intermediates in the production thereof.

The novel compounds and the process of the present invention are illustratively represented by the following formulae:

CH3 CH3 CH3 CH3 5:0 0:0 CH3 l R 011% OR ,q/ O: 0:

II t I Y on, a CHa CH3 CH5 CH3 I....@ R C 3 R Q Br- Y O O 1v m H i H i CHa CH3.

CH3 EH5 =0 .=O CH3 0R :----0 R i v v1 i it i 2,838,531 Patented June 10, 1958 ice wherein R is hydrogen or the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and wherein F represents a fluorine atom in a position selected from a. and (3.

It is an object of the instant invention to provide 6- fluoro-l7e-hydroxy-l-allopregnene-3,20 dione and 6- fluoro-17a-hydroxy-1,4-pregnadiene-3,20-dione (both the 6(1- and 6fi-fluoro isomers) and 17-esters thereof. It is another object of the instant invention to provide methods for the production of the novel compounds and novel intermediates. Other objects of this invention will be apparent to those skilled in the art to which this invention pertains.

The new products 6-fiuoro-17a-hydroxy-1,4-pregnadiene-3,20-diones and 17-esters thereof have utility as oral and parenteral progestational agents. Owing to their progesterone-like effects, the compounds of this invention fined application in cyclic therapy, where estrogenic and progestational hormones are supplied together or in succession so as to favor re-establishment of normal endometrium-ovary-anterior pituitary relationships in cases of menstrual disturbances.

In addition they affect the secretion of gonadotropins and thus regulate ovulation and endometrial and placental development and, particularly when used in conjunction with estrogens or androgens reduce fertility. The novel compounds are effective in the therapy for dysmenorrhea, amenorrhea, endometriosis, threatened abortion and related gynecological disorders.

The novel compounds of this invention can be pre pared and administered in a wide variety of oral or parenteral dosage forms, singly, or in admixture with other coacting compounds. They can be associated with a pharma'ceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixi rs. The novel compounds can also be administered topically in the form of ointments, creams, lotions and the like, with or Without coacting antibiotics, germicides or other materials forming advantageous compositions therewith.

The process of the present invention comprises: hydrogenating a 6-fluoro-17a-hydroxyprogesterone or a 17- ester thereof (1) with hydrogen in the presence of a palladium catalyst to obtain the corresponding saturated compounds 6-fluoro-17a-hydIOXypregnane-S,20-dione (II) and 6-fluoro-l7 t-hydroxyallopregnane-3,ZD-dione (III) or respectively the l7-esters thereof; brominating the thus obtained 6-fluoro-l7a hydroxyallopregnane-3,20-dione or a 17-ester thereof (III) with one to 1.2 mole of bromine per mole of steroid to give the corresponding 2- bromo-6-fluoro-17a-hydroxyallopregnane-3,20-dione or 17-esters thereof (IV); and dehydrobrominating the thus obtained 2-bromo-6-fiuoro-1Za-hydroxyallopregnane-3,20- dione or a 17-ester thereof to give 6-fluoro-17a-hydroxy- 1-allopregnene-3,20-dione or a 17-ester thereof (V). Bro' minating 6-fluoro-17u-hydroxyallopregnane-3,20-dione or a 17-ester thereof (III) with two moles of bromine per mole of steroid produces the 2,4-dibromo-6-fiuoro-17ahydroxyallopregnane-3,20-dione or 17-acylate thereof (VI) which compounds are dehydrobrominated to give 6-fluoro-17a-hydroxy-1,4 pregnadiene 3,20-dione or respectively the 17-acylates thereof (VII). The 17-esters can also be obtained by acylation of the l7-hydroxy group of the final products," 6-fluoro-l7q-hydroxy-l-allopregnene-3,20-dione and 6-fluoro-l7a-hydroxy-l,4;pregnadiene-3,20-dione, with the appropriate acylating agent in conventional manner. Alternatively 6-fiuoro-17a-hydroxy-1-allopregnene-3,20- dione of formula V, can be prepared from 6-fiuoro-17ahydroxyallopregnane-3,20-dione (III) or a l7-ester thereof by microbiological dehydrogenation for example with Septomyxa afiinis, A. T. C. C. 6737. In the samemanner microbiological dehydrogenation for example with Septomyxa afiinis of 6-fluoro-l7a-hydroxyprogesterone or a 17-ester thereof gives 6-fluoro-17a-hydroxy-l,4-pregnadiene-3,20-dione (VII). The resulting 6-fiuoro-l7a-hydroxy-l-allopregnene-3,20-dione (V) or, respectively, 6- fluoro-l7oz-hydroxy-l,4-pregnadiene-3,20-dione (VI) can, if desired, be esterified to. give the corresponding 17- esters. By a third method, for the biological dehydrogenation can be substituted a chemical dehydrogenation with selenium dioxide, often for increased yield in the presence of an element of group II of the periodic system, such as mercury, cadmium, zinc or elements of group VIII of the periodic system such as iron, nickel, cobalt or the like. The starting compounds of the present invention are 4 fractional crystallization or chromatography. Alternatively the normal and allo isomers can be conveniently separated by reaction of the mixture with pyrrolidine to form the 3-pyrrolidyl enamine. The 3-pyrro1idyl enamine of the allo isomer is the least soluble in the reaction mixture and crystallizes out leaving the 3-pyrrolidyl enamine of the normal isomer in solution. After separation, for example, by filtration, the enamine group is removed by treatment with base or with water to regenerate the 3- ketone and produce the corresponding 6-fluoro-l7a-hydroxypregnane-3,20-dione or 6-fiuoro-17ot-hydroxyallopregnane-3,'20-dione,'or the l7-esters thereof.

The allo isomer thus produced, i. e. a 6-fluoro-l7ahydroxyallopregnane-3,20 dione or a l7-ester thereof is brominated at position 2. Bromination' is conducted betweena temperature of zero to forty degrees Centigrade with room temperature being usually satisfactory. The

; reaction is carried out in an organic solvent for a period of a few minutes to about 24 hours. In the preferred embodiment of the reaction, bromine, usually in solution in the reaction solvent, is addedto a solution of the steroid, dissolved in the reaction solvent. Reaction solvents employed are, for example, acetic acid, propionic acid, chloroform, methylene chloride, benzene, chloro-' benzene, carbon tetrachloride, hexane, ether, and the like, with acetic acid being the preferred solvent. The amount of bromine used in the reaction is usually from about one to 1.2 moles of bromine per mole of steroid. it is someaddition of water and isolated by any conventional means 6-fluoro-l7u-hydroxyprogesterone and 17-esters thereof,

produced as shown in Preparations 1 through 18.

In carrying out the process of the present invention, the first step involves hydrogenation of the 4,5-double bond of a G-fluoro-l7a-hydroxyprogesterone or a l7-ester thereof. The hydrogenation can be accomplished with hydrogen in the presence of a catalyst such as palladium supported on charcoal, and is usually conducted in a solvent medium. Alkanols, hexane, acetone, methyl ethyl ketone, dioxane, acetic acid, ethyl acetate, or like organic solvents may be advantageously employed, with ethyl alcohol being preferred. The catalyst can be saturated with hydrogen prior to the introduction of the steroid or preferably the steroid, catalyst and supporting media can becontacted together in a solvent medium prior to introduction of the hydrogen. It is not necessary to conduct the reaction under pressure, although, when pressure is utilized, a hydrogen pressure of about one to 100 pounds or more is operative, a pressure of from about twenty to forty pounds is preferred. Any suitable temperature between about zero and 100 degrees centigrade may be employed, with room temperature being satisfactory. Hydrogenation is continued until approximately one molar equivalent of hydrogen has been absorbed. The catalyst is then separated from the solution by filtration and the hydrogenated products are isolated by removal of the solvent. Usually the crude hydrogenation product is a mixture containing both the normal and the allo isomers, i. e 6-fluoro-l7a-hydroxypregnane-3,20-dione and 6-fluoro-l7a-hydroxya1lopregnane-3,20-dione or the 17-esters thereof. -The isomers are separated by conventional means 'such as for example,

such as filtration or extraction with a water-immiscible solvent. The crude product, 2-bron1o-6a.-fiuo1'o-l7a-hydroxyallopregnane-3,20-dione or a l7-ester thereof, can be purified by crystallization from an organic solvent or it can be used directly in the dehydrobromination step without purification.

In the dehydrobromination step of the present inven tion, the starting 2-bromo steroid is usually dissolved in the dehydrohalogenation agent, if it is a liquid solvent for the steroid, or both the dehydrohalogenation agent and the steroid are dissolved in a substantially inert diluent and then heated, usually at a temperature substantially above room temperature, -e. g., between about fifty and about 250 degrees centigrade, for about fifteen minutes to several hours, although the reaction ordinarily begins as soon as the heating commences.

Dehydrohalogenation agents which may be employed include, dimethylformamide, often in presence of lithium chloride, basic substances such as potassium acetate, pyridine and the alkyl pyridines, e. g., the picolines, fi-lutidines, 0a,}3-C0llidll185,.y-C0llidii16S, and the like.

Ordinarily, the dehydrohalogenation agent is employed in a ratio to the starting steroid of about four to one or greater. On completion of the reaction, the reaction mixture is cooled and poured into a dilute solution of an acid, preferably a mineral acid, e. g., sulfuric acid. The product, 6-fiuoro-l7oc-hydroxy-l-allopregnene-3,20- dione or a 17-ester thereof, is extracted from the acid mixture with a water-immiscible solvent such as, for example, methylene chloride and is purified by conventional means such as recrystallization, chromatography, or both.

The preparation of 6-fiuoro-l7a.-hydroxy-l,4-pregnadiene-3,20-dione or l7u-esters thereof from 6-fiLlO10-17ahydroxyallopregnane-3,ZO-dione or l7u-esters thereof is carried out in the same manner as for the 6-fiuoro-l7ahydroxy-l-allopregnene-3,20-dione and l7-esters except that in the bromination step from 2 to 2.5 moles of bromine per mole of steroid are employed, thus causing the production of the 2,4-dibromo compound, 2,4-dibromo 6-fiuoro-17a-hydroxyallopregnane-3,20-dione or 17-esters thereof (compound VI):

Alternatively the compounds of the present invention, can be prepared by microbiological or selenium dioxide dehydrogenation at the l-position. Dehydrogenationof 6mfiuoro-17a-hydroxyallopregnane-3,20-dione or 6/3-fiuoro- 17d' hydroxyallopregnane 3,20- dione with Septomyxa aflinis, A. T. C. C. 6737 is productive of 6a-fiuoro-l7ahydroxy-1-allopregnene 3,20-dione or respectively 6fifluoro-l7ot-hydroxy-1-allopregnene-3,ZO-dione. Dehydrogenation of 6a-fiuoro-17a-hydroxyprogesterone with Septomyxa afiinis A. T. C. C. 6737 or selenium dioxide is productive of 6-fluoro-17a-hydroxy-1,4-pregnadiene- 3,20-dione.

The compounds of this invention, represented by Formulas V and VII, maybe utilized either as the free alcohols or as the esters. Esterification is carried out by methods well established in the art for esterifying tertiary hydroxyl groups, e. g., Huang-Minion et al., J. Am. Chem. Soc., 74, 5394- (1952). Huang-Minlon et al. describe both a cold method and a hot method both of which are useful in the-esterification of G-fiUOIO-l'lahydroxy-l-allopregnene-3,20-dione or 6-fluoro- 17a -hydroxy-1,4-pregnadiene-320-dione. Esterification is accomplished by allowing the hydroxy compounds to react with the anhydride. or the acyl halideof an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, for example, a saturated straight-chain aliphatic acid, such as acetic, propionic, butyric, valeric, hexanoic, lauric; a saturated branched chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric; a cycloaliphatic saturated acid, e. g., cyclohexanecarboxylic acid,.13-cyclopentylpropionic; an alkaryl acid, e. g., phenylacetic, 2-

phenyl-propionic, 0-, m-, and p-toluic; a saturated dibasic PREPARATION l 17a-hydr0xyprogester0ne acetate One hundred grams (0.303 mole) of l7a-hydroxyprogesterone was dissolved in 1340 milliliters of acetic acid in a two liter round bottom flask equipped with stirrer, thermometer, and nitrogen inlet and outlet. Solution was accelerated by stirring and warming to about fifty degrees centigrade. The solution was cooled to eighteen to twenty degrees centigrade, and 340 milliliters of acetic anhydride added. The system was flushed with nitrogen, and forty grams of p-toluenesulfonic acid added with vigorous stirring and cooling to below about 22 degrees centigrade. The reaction mixture was allowed to stand for a period of two hours and then poured into six liters of ice water and was kept at zero to five degrees centigrade for a period of about thirteen to fifteen hours, whereupon the crude acetate was filtered oif and washed several times with water. The product weighed 101 percent of theory and melted at 2l7to 245 degrees centigrade. It was purified by recrystallization from methanol containing aqueoussodium hydroxide to yield 76 grams of the purified l7a-hydroxyprogesterone l7-acetate of melting point 243 to 248 degrees centigrade and rotation [aJ plus 69 degrees in chloroform.

PREPARATION 2 1 7a-hydroxyp rogesterone 1 7-plzenylacetate In the same manner as the above preparation, 17ahydroxyprogesterone 17-phenylacetate is prepared using a mixture of phenylacetic acid (500 grams) and phenyl acetic anhydride (SOOgrams). One thousand milliliters of'benzene is employed to provide a liquidi'reaction mix= ture. The product, l7u-hydroxyprogesterone 17-phenylacetate isrecovered in good yield'eby adding water to the reaction mixture, separating theorganic layer after it has stood for a period of about two hours, then washing the organic layer with water followed by an aqueous solution of sodium carbonate, followed again by a waterwash and finally evaporating to dryness. The residual crude product is purified by recrystallization from methanol to give 17a-hydroxyprogesterone 17-phenylacetate.

PREPARATION 3 1 7a-hydroxyprogesterone 17-f0rmate PREPARATION 4 17a-hydroxyprogesterone capr'oate Following the procedure of Preparations 1 and 2, 17ahydroxyprogesterone caproate is prepared using a mixture of caproic acid and caproic anhydride.

In a manner corresponding to that of the foregoing preparation l7ot-hydroxyprogesterone phenylpropionate,

17a-hydroxyprogesterone 2-furoate, l7a-hydroxyprogesterone acrylate, 17a-hydroxyprogesterone valerate, 17ahydroxyprogesterone trimethylacetate, l7u-hydroxyprogesterone t-butylacetate, 17a-hydroxyprogesterone cyclopentylcarboxylate, 17a-hydroxyprogesterone ethylbutyrate, l7a-hydroxyprogesterone cyclohexylacetate, l7a-hydroxyprogesterone o-toluate, 17a-hydroxyprogesterone mono glutarate, 17a-hydroxyprogesterone B-cyclopentylpropionate, 17a-hydroxyprogesterone mono-,8,;9-dimethylglutarate, l7a-hydroxyprogesterone laurate, l7a-hydroxyprogesterone butyrate, 17u-hydroxyprogesterone propionate, 17a-hydroxyprogesterone isovalerate, 17ot-hydroxyprogesterone enanthate and l7u-hydroxypro'gesterone caprylate are prepared by dissolving 17a-hydroxyprogesterone in a solution comprising a mixture of the appropriate acid and its anhydride together with p-toluenesulfonic acid. The crude ester is isolated in accordance with the procedure of the foregoing preparations, if necessary subjectedto a selective hydrolysis of the enol ester group, and recrystallized to give the l7a-hydroxyprogesterone ester. If the corresponding acid or its anhydride is solid, an inert solvent such as benzene, chloroform or dioxane can be added to'eiiect solution and to provide a liquid esterification reaction medium.

PREPARATION 5 17a hydroxyprogesterone 17 acetate, 3 ethylene ketal A solution was prepared containing ten gramsof 17ahydroxyprogesterone l7-acetate in fifty milliliters of chloroform. Thereto was added milliliters of ethylene glycol containing 500 milligrams of paratoluenesulfonic acid monohydrate. The mixture was concentrated with stirring at atmospheric pressure under nitrogen until the temperature reached about 75 degrees centigrade. The pressure was then reduced to remove th'e'last traces of chloroform. Forty-eightmilliliters of distillate was collected over one half hour as the product precipitated. Themixture was then cooled with stirring, one milliliter of pyridine was added followed by 200 milliliters of five percent aqueous sodium carbonate'solution. The mixture was filtered and the product washed with sodium carbonate. The moist filter cake was taken up in methylene chloride. The organic layer was removed, washed with Water, dried over anhydrous magnesium sulfate, and evaporated to give a white crystalline cake containing 10.9 grams of crude l7ot-hydroxyprogesterone l7-acetate, S-ethylene ketal of melting point 240 to 244 degrees centigrade and rotation [od minus 39 degrees in chloroform.

Analysis.Calcd. for C H O C, 72.08; H, 8.71. Found: C, 71.56; H, 8.47.

PREPARATION 6 17a hydroxyprogesterone 17 phenylacetate, 3 ethylene ketal A solution was prepared containing five grams of 17ahydroxyprogesterone 17-phenylacetate in 100 milliliters of benzene, ten milliliters of ethylene glycol and 0.25 gram of para-toluenesulfonic acid monohydrate. This mixture was refluxed for a period of seventeen hours using a calcium carbide water-trap to remove the water formed in the reaction. After this period of reflux one milliliter of pyridine was added to the solution, and the mixture was cooled to room temperature. The lower glycol layer was separated and washed with benzene. The benzene layer and the washings with benzene were combined, washed with five percent sodium carbonate solution, water and saturated sodium chloride solution. After being dried over anhydrous magnesium sulfate, the solution was concentrated to dryness at reduced pressure. The residue was recrystallized twice from hot methylene chloride, and once from acetone to give pure 17a-hydroxyprogesterone 17-phenylacetate, 3-ethylene ketal.

In the same manner as shown in Preparation 5, other 17a-hydroxyprogesterone 17-acylate, 3-alkylene ketals are prepared by reaction at reflux temperature solutions of 17a-hydroxyprogesterone acylates in benzene, toluene, hexane, heptane, or other inert organic solvents with 1,2- alkane diols or 1,3-alkane diols such as butane-1,2-diol, butane-1,3-diol, pentane-1,2- and 1,3-diol, hexane-1,2- and 1,3-diol, heptane-l,2- and 1,3diol, octane-1,2- and 1,3-diol, or other alkane diols of the formula:

wherein n is an integer having a value from one to two, inclusive, and R and R are selected from the group consisting of hydrogen and lower alkyl radicals containing up to six carbon atoms and wherein the total number of carbon atoms in the alkane diol is up to and including eight carbon atoms, in the presence of a strong acid such as toluenesulfonic acid, ortho-chlorobenzenesulfonic acid, sulfuric acid, and the like, to obtain the corresponding l7ot-hydroxyprogesterone 17-acylate, 3-alkylene ketal. Representative 17a hydroxyprogesterone 17 acylate, 3 alkylene ketals include the 17a hydroxyprogesterone 17 caproate, 3,20 bis (1,3 propylene ketal); 170L- hydroxyprogesterone 17 hemisuccinate 1,2 and 1,3- butylene diketal; 17a hydroxyprogesterone 17 propionate 1,2-, 1,3- and 2,3-pentylene diketal; 17a-hYd1OXY- progesterone 17 phenylpropionate; 3 ethylene ketal; 17oz hydroxyprogesterone 17 butyrate and 17 valerate, 3 ethylene ketals; 17a hydroxyprogesterone 17 benzoate, 3 propylene ketal; 17a hydroxyprogesterone 17- hexanoate and cyclohexylformate, 3-ethylene ketals; 17ahydroxyprogesterone 17,-laurate, 3-ethylene and 3-propylene ketals and the like.

PREPARATION 7 centigrade, with 42 milliliters of cold forty percent peracetic acid containing 4.2 grams of sodium acetate. The mixture was allowed to stir overnight at room temperature, the layers were then separated, the peracetic acid layer after dilution with water was extracted with benzene three times and the combined benzene layers were washed with cold dilute sodium hydroxide and water and thereupon dried over anhydrous sodium sulfate. The dried benzene solution was then evaporated to dryness and the thus obtained residue recrystallized once from methylene chloride-ether and then from ethyl acetate to give 2.7 grams of the a-epoxide, 5ot,6a-oxido-l7a-hydroxypregnane-3,20-dione Not-acetate, 3-ethylene ketal of melting point 224 to 228 degrees centigrade and rotation [a] minus 63 degrees in chloroform.

Analysis.-Calcd. for C H O C, 69.41; H, 8.40. Found: C, 69.46; H, 8.81.

PREPARATION 8 5a,6a oxide 17cc hydroxypregnane 3,20 dione 17- phenylacetate, 3 ethylene ketal A solution was prepared by heating five grams of 17mhydroxyprogesterone l7-phenylacetate, 3-ethylene ketal and milliliters of benzene. After the solution was effected the flask was cooled to five degrees centigrade and a mixture of one gram of sodium acetate and 25 milliliters of peracetic acid solution (40 percent) was added with stirring. The reaction mixture was stirred in the ice bath for five hours. The lower peracid layer was separated, diluted with water, and extracted twice with'benzene. The upper layer was neutralized by the addition of cold ten percent sodium hydroxide solution while stirring in an ice bath. The rate of addition of the sodium hydroxide was regulated to keep the temperature below ten degrees centigrade. The lower layer was then extracted with benzene and the combined benzene extracts washed. with cold ten percent sodium hydroxide solution and then with saturated sodium chloride solution. All the aqueous layers were washed again with the same portion of benzene. The combined benzene layers were dried over anhydrous magnesium sulfate and concentrated to dryness at reduced pressure. The residue was recrystallized from acetone and methylene chloride and then from ethyl acetate to give 50t,60t-OXldO-17ahydroxypregnanc-3,ZO-dione l7-phenylacetate, S-ethylene ketal.

PREPARATION 9 5tz,6u oxide 17o: hydroxypregnalze 3,20 ione I7- rzcetate, 3-pr0pylene ketal In the same manner given in Preparation 8, reacting l7e-hydroxyprogesterone 17-acetate, 3-propylene ketal with peracetic acid and anhydrous sodium acetate in chloroform solution produced 506,60t-OXldO-L-hydI'OXypregnane-3,20-dione 17-acetate, 3-propylene ketal.

In the same manner as shown in Preparations 8 and 9 other 5a,6ot-oxido-l7u-hydroxypregnanc-3,20-dione 17- acylates, 3-ketals are prepared by reacting the corresponding 17a-hydroxyprogesterone l7-acylate ketals with a peracid, such as performic, peracetic, perpropionic, perbenzoic, perlauric or monoperphthalic acid, at low temperatures usually between minus ten and plus ten degrees centigrade. Representative compounds thus prepared comprise: 5u,6a-oxido-17u-hydroxypregnane-3,20- dione, l7-caproate, 3-(l,3-propylene ketal); 50:,6a-0Xld0- 17ct-hydroxypregnanc-3,ZO-dione l7-formate, 3-(l,2-butylene ketal); Saba-oxide-l7u-hydroxypregnane-3,20-dione l7-propionatc, 1,2-, 2,3-, 2,4- and 1.3-pentylcnc ketals; 5a,6tx-oxido-l7ot-hydroxypregnane-3,ZO-dione l7- phenylpropionate, 3-ethylene ketal; 5u,6u-oxido-l7a-l1ydroxypregnanc-3 ,ZO-dione l7-( 3-cyclopentylproprionate) l7-butyrate and 17-valerate, 3-ethylene ketal; 50,60coxido-l7bt-hydroxypregnane-3,20-dione l7-benzoate, 3- propylene ketal; 5a,6a-oxido-17a-hydroxypregnane-3,20-

dione 17-hexanoate and cyclohexylformate, 3'-ethylene ketals; a,6u-oxido-17a-hydroxypregnane-3,20-dione- 17- laurate, 3-ethylene and 3-propylene ketals and the like;

PREPARATION 5 a,1 7a-dihydr0xy-6 p-fluoropregnane-iZO dione tate, 3-ethylene ketal 1 7-ace- PREPARATION 1 1 501,170; dihydroxy 6p fluoropregnane 3,20 dione 17- phenylacetate, 3-ethylene ketal A solution of 400 milligrams of 5a,6a-oxido-17a-hydroxypregnane-3,20-dione l7-phenylacetate, 3-ethylene ketal in five milliliters of alcohol-free chloroform was cooled to minus fifteen degrees centigrade. To. the cooled solution was added 2.5 milliliters of an ice salt solution of about 100 milligrams of anhydrous hydrogen fluoride ini five milliliters of alcohol-free chloroform. The reaction mixture was stored at minus fifteendegrees centigradefor four hours with occasional stirring. The solu-: tion was then washed at about zero degrees centigrade with aqueous sodium bicarbonate and then with water. The washed chloroform solution was dried and then distilled to dryness, leaving a residue of 5u-,17a-dihydroxy- 6p-fluoropregnane-3,20dione 17-phenylacetate, Ii-ethylene ketal.

PREPARATION 12 5 11,1 7udihydroxy-65-fluoropregnane-3,20-dione 1 7 ace rate, 3pr0pylene ketal In a fifty milliliter polyethylene bottle, cooled with Dry Ice-acetone, was placed 3.5 grams of anhydrous hydrogen fluoride, followed slowly with 2.5 milliliters of chilled chloroform and seven milliliters of tetrahydrofuran. To this solution was added two gramsof' 5a,6uoxido-l7a-hydroxypregnane 3,20 dione' 17 acetate, 3- propylene ketal; The violet solution was then kept'for two hours at minus ten degrees centigrade and then poured into excess aqueous sodium bicarbonate. The product was extracted from the aqueous mixture with three 25-rnilliliter portions of methylene chloride, the methylene chloride extracts combined, washed three times with water, evaporated to dryness andthe thus obtained material twice recrystallized from ethylene chloride and ethyl acetate to give 5a,17a-dihydroxy-GB-fluoropregnane- 3,20-dionel7-acetate, 3-propylene ketal.

In the same manner as shown in Preparations 10 through 12, inclusive, treating other 50:,6a-0Xid0-17ochydroxypregnane-3,20-dione 17-acylates 3-alkylene ketals with hydrogen fluoride, either in the free state or produced in situ, results in the corresponding 5a,17a-dihydroxy 6/8 fluoropregnane 3,20 dione 17 acylate, 3-alkylene ketal. Representative compounds thus prepared comprise 5a,17e-dihydroxy-6e-fiuoro-3,20-dione 17- caproate 3 (1,3 propylene ketal); 5a,17a-dihydroxy- 65 fiuoropregnane 3,20 dione 17 formate, 3 (1,2-, 2,3- and 1,3-butylene ketals); 5a,l7a-dihydroxy-6fi-fluoropregnane-3,-20-dione l7-propionate, 1,2-, 2,3-, 2,4- and 1,3-pentylene ketals; 5u,17a-dihydroxy 6/3 fluoropregnane-3,20- .dione. 17-phenylpropionate, 3-ethylene ketals; 50;,170; dihydroxy. 6p fluoropregnane 3,20 dione 17-(/S-cyclopentylpropionate), 17-butyrate and 17- valerate, 3 ethylene ketals; 5u,17a dihydroxy 6,6 fluoropregnane-3g2'0-dione 17-benzoate, 3-pr'opylene ketal; 5a, Nix-dihydroxy 6,8 fiuoropregnane 3,20 dione 17-" hexanoate and cyclohexylformate, 3-ethylene ketals; 5a, 170: dihydroxy 6,8 fluoropregnane 3,20 dione 17- laurate, 3-ethylene and 3-propylene ketals and the like.

PREPARATION 13 5 (1,1 7u-dihydr0xy-6B-flu0r0pregnane-3,20-dione 1 7-acetate The crude 51x,17int-dihydroxy-6fi-fluoropregnane-3,20- dione 17-acetate, 3-ethylene ketal of Preparation 10 was dissolved in twenty milliliters of percent ethanol and thereto. was added 0.5 milliliter of one normal sulfuric acid. The mixture was warmed for a period of twenty minutesthen diluted with milliliters of water and the precipitated material collected and filtered. The thus produced 5a,l7a dihydroxy 613 fiuoropregnane 3,20- dione l7-acetate was recrystallized from ethanol and had a melting point of 260 to 262 degrees centigrade.

PREPARATION 14 5 04,1 7 a-dihydroxy-6 8-flu0r0pregnane-3 ,20-z ii one 1 7 phenylacemte A solution was prepared containing ten grams of 5a,17a dihydroxy 6(3 fiuoropregnane 3,20 dione l7- phenylacetate, B-ethylene ketal in 100 milliliters of boiling acetone. Thereto was added ten milliliters of one normal sulfuric acid in portions under swirling and seedingwith product. Boiling was continued for a period of two minutes and the mixture was allowed to stand at room temperature. Thereafter the mixture was diluted with 400 milliliters of water, chilled and filtered; The precipitate was washed with water, dilute ammonium hydroxide and water, dried in a vacuum oven overnight, and then twice recrystallized from acetone to give 50,17otdihydroxy 6 8 fiuoropregnane 3,20 dione 17 phenylacetate. 7

PREPARATION 15 6a-flu0r0-l7m-hydroxyprogesterone 17-acetate A solution of 87 milligrams of 5u,17a-dihydroxy-6flfluoropregnane-3,20-dione 17-acetate, dissolved in five milliliters of chloroform, was cooled in an ice salt bath. This solution was saturated with hydrogen chloride gas fora period of thirty minutes. Thereafter the mixture waswashed with three twenty-milliliter portions of water to renderthe solution neutral. Thereafter the-solution was dried over anhydrous magnesium sulfate, and evaporated to dryness to give a crystalline material which was recrystallized from ethyl acetate to give 6ot-fi1l0lO-l7ahydroxyprogesterone 17-acetate of melting point 253 to 256 degrees centigrade and rotation [al plus 66 degrees in chloroform 5 235 my; A 15,575 Analysis.Calcd. for C H FO F, 5.07 Found:

PREPARATION l6 6u-flu0r0-17a-hydroxyprogester0ne 17-phenylactate In the same manner given in Preparation 15, dehydrating 501,17a-dihydroxy-6/3-fiuoropregnane-3,20-dione 17- phenylpropionate resulted in 6u-fluoropregnane-3,20-dione l7-phenylacetate.

PREPARATION 17 6 fi-fluoro-I 7a-hydr0xypr0gester0ne 1 7 acetate To a solution of 200 milligrams of 5a,l7oc-dihyd1OXy- 6pt-fluor0pregnane-3,20-dione l7-acetate in forty milliliters of 95 percent ethanol was added two milliliters of 0.1 normal sodium hydroxide solution. The mixture was kept for four hours at a temperature of about 35 degrees centigrade and .thereupon neturalized with a few drops of acetic. acid.and poured into 100 milliliters of ice water. The precipitated crude p-fluoro-17a-hydroxyprogesterone 11 l7 acetate was recrystallized twice from ethyl acetate- SkellysolveB hexane to give pure 6B-fluoro-l7a-hydroxyprogresterone 17-acetate of melting point 196 to 199 degrees centigrade and rotation [04] minues 19 degrees (chloroform) In the same manner given in Preparation 17, treating other 5a,l7u-dihydroxy-6,6-fluoropregnane-3,ZO-dione 17- acylates with dilute alkali or dilute acids under mild conditions produces the corresponding 6fi-fluoro-17a-hydroxyprogesterone acylates. In this manner are produced the following representative compounds: 6fl-fluoro- Hen-hydroxyprogesterone 17-caproate, formate, propionate, isobutyrate, valerate, octanoate, decanoate, laurate, acrylate, crotonate, benzoate, phenylpropionate, phenylacetate, trimethylacetate, B-cyclopentylpropionate, hemisuccinate, fl,fi-dimethylglutarate and the like.

PREPARATION 1s 6 afluoro-1 7a-hydroxyprogesterone A solution of 6u-fiuoro-Not-hydroxyprogesterone l7- acetate (200 milligrams) in four milliliters of 95 percent ethanol and 0.5 milliliter of water containing 100 milligrams of potassium hydroxide was allowed to stand at room temperature (approximately 25 degrees centigrade). Thereafter the mixture was neutralized by the addition of sufficient acetic acid and poured into fifty milliliters of ice water. The ice water solution was extracted with three tenmilliliter portions of methylene chloride. The methylene chloride solutions were combined, washed with water, dried over anhydrous sodium sulfate and evaporated. The thus obtained residue was recrystallized three times from methanol to give 6a-fiuoro-17ahydroxyprogesterone.

In the same manner as shown in Preparation 18 other oa-fluoro-l7ot-hydroxyprogesterone l7-acylates can be hydrolyzed at room temperature with a base such as sodium or potassium hydroxide, sodium or potassium carbonate or the like to give 6a-fiuoro-Hot-hydroxyprogesterone.

The 6fi-fluoro epimer, 6,8-fluoro-Not-hydroxyprogesterone, is obtained by treating 6p-fluoro-l7a-hydroxyprogesterone 17-acetate with on equivalent of anhydrous potassium methoxide in absolute methanol, allowing to stand for minutes and adding one equivalent of water. Thereafter the aqueous mixture is neutralized with hydrochloric acid, diluted with water and filtered. The crude material is purified by recrystallization from methanol to give pure 6fi-fluoro-Not-hydroxyprogesterone.

EXAMPLE I A solution of five grams of 6ot-methyl-l7u-hydroxyprogesterone in 200 milliliters of 95 percent ethanol, containing 0.5 gram of five percent palladium on charcoal, was hydrogenated at room temperature (about 25 degrees centrigrade) and thirty pounds pressure until the uptake of hydrogen ceased. The catalyst was removed by filtration and the precipitated material washed with alcohol and the washings added to the filtrate. The filtrate was thereupon evaporated to dryness. The residue was dissolved in 25 milliliters of hot methanol containing three milliliters of pyrrolidine, refluxed two minutes under nitrogen, and scratched or seeded. A crystalline precipitate consisting of the 3-enamine of 60t-fll10I'0-l7ochydroxyallopregnane-3,20-dione precipitated and was collected, washed with cold methanol and dried. The enamine group was removed by dissolving the 3-enamine of 6a-fiuoro-17a-hydroxyallopregnane-3,20-dione in methanol containing two percent aqueous sodium hydroxide and warming the solution to fifty degrees centigrade for a period of twenty minutes. After neutralizing with acetic acid, the solvent was removed by evaporation, the residue was taken up in ether and water and the ether layer concentrated to dryness. Recrystallization of the crude 6u-fiuoro-17a-hydroxyallopregnane-3,20-dione gave the pure product 6a-fiuoro-17a-hydroxyallopregnane-3,20- dione.

The 3-enamine of 6a-fiuoro-l7a-hydroXypregnane-3,20- dione (normal) does not precipitate and can be obtained from the solution from which the enamine of the allo compounds have been removed in conventional manner: i. e. by adding .two milliliters of two percent aqueous sodium hydroxide and heating for twenty minutes to fifty degrees, neutralizing with acetic acid and removing the solvent by evaporation. The thus obtained residue is dissolved in methylene chloride and water and the methylene chloride layer separated and evaporated to dryness to give crude 6-fluoro-17a-hydroXypregnane-3,ZO-dione (normal) which is recrystallized from acetone and Skellysolve B to give the pure 6-fluoro-17a-hydroxypregnane- 3,20-dione.

In the same manner as shown in Example 1 hydrogenating 6/9 fluoro 17a hydroxyprogesterone affords the 6,8 fluoro 17cc hydroxyallopregnane 3,20 dione and 618 fluoro 17a hydroxypregnane 3,20 dione (normal).

EXAMPLE 2 2-br0m0-6ot-flu0r0-17a-hydr0xyall0pregnane-3,20-di0ne A solution containing 14.5 grams of bromine in 150 milliliters of glacial acetic acid was added with slow stirring to 30.5 grams of 60: fluoro 17a hydroxyallopregnane-3,20-dione, dissolved in three liters of acetic acid to which was added a few drops of 4 normal hydrogen bromide solution in acetic acid. A few minutes after the addition had been completed water was added and the fluoro 17a hydroxyallopregnane 3,20 dione instead of the 60: epirner and brominating with bromine in glacial acetic acid in the presence of hydrogen bromide produces the 2 bromo 6p fluoro 17a hydroxyallopregnane-3,20-dione.

EXAMPLE 3 2,4-dibr0mo-6a-flu0r0-17a-hydi'oxyallopregnane- 3,20-dione In the same manner as shown in Example 2, reacting 6a fluoro 17oz hydroxyallopregnane 3,20 dione with bromine however, using thirty grams of bromine for 30.5 grams of steroid in the presence of one milliliter of four normal hydrogen bromide solution in acetic acid and allowing the mixture to stand overnight resulted in 2,4-dibromo 60c fluoro 17a hydroxyallopregnane 3,20- dione which was recovered by adding water to the reactionmixture to precipitate the crude compound, recovering the precipitate by filtration, washing the precipitate with water and drying it. The crude material was recrystallized from ethyl acetate Skellysolve B to give pure 2,4 dibromo 6oz fluoro 17a hydroxyallopregnane- 3,20 dione.

In the same manner using the Gil-isomer, 6;8-fluoro-l7ahydroxyallopregnane-3,20-dione and treating with two moles of bromine per mole of steroid in acetic acid in the presence of hydrogen bromine resulted in the 2,4-dibromo-Gfl-fiuoro-17a-hydroxyallopregnane-3,20-dione.

EXAMPLE 4 fia-fluoro-I 7a-hya'r0xy-1-allopregnene-3,20-dione A solution was prepared containing in 210 milliliters of redistilled dimethylformamide twenty-one grams of 2 bromo 6oz fluoro 17a hydroxyallopregnane- 3,20-dione. The mixture was heated on the water bath for two hours, was thereupon cooled and poured into cold water. The aqueous reaction mixture was then extracted with 250 milliliter portions of methylene chloride. The

. 13 methylene chloride solution was washed with three 100 milliliter portions of water, dried over anhydrous sodium sulfate and evaporated to a small'volume. The solution was then diluted. to 700milliliters with ,Skellysolve B and chromatographed over 500 grams of Florisil anhydrous magnesium silicate. Volumes of 700 milliliters of Skellysolve B hexanes containing increasing proportions of acetone wereused for chromatography. Those fractions exhibiting a ML; at 228 to 232 millimicrons were. combined, concentrated to dryness and. the. thusobtained dryresidue recrystallized to give pure 60t-fluOIO- 17a-hydroxy-l-allopregnene-3,20-dione.

'In like manner the 6fl-isomer, '6p-fiuoro-l7a-hydroxy- 1-allopregnene+3,20*dione was prepared by dehydrobrominating with dimethylformamide the corresponding 2- bromo- 6,8-fluoro-l7a-hydroxyallopregnane-3,20-dione.

EXAMPLE 6 Ot-flHOIO 17a-hydroxy-1-allopregnene-3,20-di0ne 17-acetate (A) In the samemanner as shown in Example 1 6a.- fluoro. 17a hydroxyprogesterone 17 acetate was hydrogenated with hydrogen in the presence of a palladium catalyst suspended on charcoal to give the 6a-fiuoro-l7ahydroxyallopregnane-3,20-dione Hot-acetate.

In the same manner as shown in Example 2 6u-fluoro- 17oz hydroxyallopregnane 3,20 dione 17 acetate was brominated with bromine and; glacial acetic acid inthe presence of hydrogen ubromide to give the corresponding 2 bromo 60c fluoro 17a hydroxyallopregnane 3,20- dione 17,-acetate.

In the same manner as shown in Example 4 dehydrobrominating with dimethylformamide the 2 brom'o-6afluoro 17cc hydroxyallopregnane 3,20 dione 17- acetate results in 6a fluoro f 1 70: hydroxy 1 allopregnene-3,20-dione 17-acetate.

(B) A solution of one gram of 6a fluoro 17oz hydroxy 1 allopregnene 3,20 dione in twenty milliliters of acetic anhydride and one gram ofpara-toluene sulfonic acid was allowedto stand overnight for eighteen hours at a temperature of about 22 degrees centigrade. The solutionwasdiluted with twenty milliliters of methanol and,0.3.milliliter of concentrated hydrochloric acid andwas refluxed for one hour under nitrogen. Twenty milliliters of pyridine was added and the mixture was evaporated to dryness. The crude product was recrystallized from methanol to give 6u-fiuoro-l7ot-hydroxy-1-allopregnene-3,20-dione 17-acetate.

In the same manner asshown in Example 5 using either the method described under (A) or the method described under (B) other esters of 6a-fluoro-l7a hydroxy-l-allopregnene-3,20-dione are obtained such as the l7-propio-. nate, butyrate, valerate, hexanoate, hyptanoate, octanoate, benzoate, phenylacetate, fl-cyclopentylpropionate, trimethylacetate, launate, decanoate, cinnamate, propiolate. To obtain, esters of unsaturated acid such as the 6a-fluoro- 1 7a: acetoxy 1 allopregnene 3,20 dione l7 acrylate, crotonate, undecylenate, propiolate, Z-butynoate, undec olate, or .the like or ester of dibasic unsaturated acids such as the maleate, citraconate, direct acylation of the 60: fluoro 17a. hydroxy 1 allopregnene 3,20 dione (methodB) is preferred since in the other method bromination may occur on the unsaturated acid without subsequent removal of hydrogen bromide in the acyl group.

Using as starting material 6/3-isomers such as Gp-fluoro- 17a hydroxy 1 allopregnene -3,20 dione in the method of Example 5B produces the acetate, propionate, benzoate, phenylacetate, phenylpropionate, cinnamate and other esters of 6/3 fluoro 17a hydroxy 1 allopregnene-3,20-dione.

14 EXAMPLE 6 6 u-fluoro-J 7a-hydroxy-I ,4-pregnadiene-3,ZO-dione A solution of ten grams'of 2,4-dibromo-6u-fluoro-l7ahydroxyallopregnane-3,20-dione was heated for two hours in milliliters of redistilled dimethylformamide and ten grams of lithium chloride, then cooled, poured into cold water and the aqueous solution extracted with methylene dichloride. The methylene chloride solution was washed thoroughly with water, dried, evaporated over anhydrous sodium sulfate, and chromatographed over 500 grams of Florisil anhydrous magnesium silicate'and was eluted with Skellysolve B hexanes containing increasing-proportions of acetone as described before.

The fractions showing a M; at 238 to 246 millimicrons where combined, evaporated to give a residue and the thus obtained residue several times recrystallized from methanol to give 6a-fluoro-l7oz-hydroxy-l,4-pregnadiene- 3,20-dione-.

EXAMPLE 7 6a fluoro 17cc hydroxy 1,4 pregnadiene 3,20-

dione 17-acetate EXAMPLE 8 6u-fluora-17a-hytlr0xy-1,4-pregmrdiene-3,20-di0ne 1 7- acetate A mixture containing ten grams of 6OL-fll1OIO-17a-hydroxy-4-pregnene-3,ZO-dione 17-acetate in 500 milliliters of tertiary butyl alcohol, five milliliters of glacial acetic acid and four grams of selenium dioxide was warmed at reflux for'24 hours. An additional four gram portion of the selenium dioxide was added and warming was continued for another 24 hour period. The reaction mixture was then cooled and filtered. The filtrate was concentrated to about milliliters and then slowly diluted with 850 milliliters of water. The resulting precipitate was isolated by filtration. The precipitate was dissolved in 300 milliliters of ethyl acetate, then washed with 400 milliliter portions of freshly prepared cold ammonium sulfide, dilute ammonium hydroxide, then water, then dilute hydrochloric acid and water. The solution was then dried over anhydrous sodium sulfate and evaporated to give about nine grams of crude 6oc-fl110rO-l7oc-hY- droxy-1,4-pregnadiene-3,20-dione l7-acetate. The crude material was purified by recrystallization from Skellysolve B hexanes and acetone.

EXAMPLE 9 6a-fl'uor0-1 7a-hydr0xy-1-all0pregnene-3,ZO-dione Twelve liters of a mediumconsisting of one percent Cerelose dextrose, two percent corn steep liquor of sixty percent solids, were adjusted .to a pH of 4.9 with sodium hydroxide. Ten milliliters of lard oil containing 0.1 to two percent octadecanol was added to prevent foaming. The medium was steam sterilized at fifteen pounds pressure for thirty minutes. Upon cooling the sterile medium was inoculated with a 24-hour growth of spores of Septomyxa afiinis A. T. C. C. 6737. The medium was agitated, and sparged with sterile air at the rate of one liter of air per minute. After culturing at room temperature for 24 hours, the pH was about 7.3. To this 24- hour culture there was added six grams of 6oL-fll1Ot0-17othydroxyallopregnane-3,20-dione, dissolved in 130 milliliters of acetone. Fermentation of the 6a-fluoro-17ahydroxyallopregnane-3,20-dione was maintained for 24 hours. The fermentation broth was then strained through gauze to separate the mycelium. The mycelium was washed once with one liter of acetone and then twice with one-liter portion of methylene chloride. The acetone and methylene chloride washings were combined with an additional four liters of methylene chloride and this seven liters of extract and solvent was then used to extract the filtered beer. Upon separation of the extract from the beer, the beer was twice more extracted with three-liter volumes of methylene chloride. acetone and methylene chloride extracts were combined and washed with 1200 milliliters of two percent sodium bicarbonate solution, and then with 1200 milliliters of water. The washed solvent extract was then dried with anhydrous sodium sulfate and evaporated to leave seven grams of extract. The extract was dissolved in 230 milliliters of benzene and fractionated over a column of 300 grams of alumina using 230-milliliter portions of developing solvent (Skellysolve B containing increasing proportions of acetone). Those fractions exhibiting a ML, at. 228 to 232 millimicrons were combined, evaporated to a residue and the residue recrystallized two times from methanol to give pure 6afluoro-17a-hydroxyl-allopregnene-3 ,20-dione.

EXAMPLE 6a-fluor0-1 7oc-hydr0xy-1,4-pregnadiene-3,ZO-dione 17- benzoate A mixture containing two grams of 6oz-fll10l'0-17m-hydroxyprogesterone 17-benzoate five milliliters of glacial acetic acid, four grams of selenium dioxide and four grams of mercury was warmed upv for a period of 24 hours. The reaction mixture was then cooled and filtered. The filtrate was concentrated to twenty milliliters and then diluted with 150 milliliters of water. The resulting precipitate was recovered by filtration. The precipitate was then dissolved in sixty milliliters of ethyl acetate and washed with four 25 milliliter portions of freshly prepared cold ammonium sulfide, dilute ammonium hydroxide, water, dilute hydrochloric acid and water. The solution was then dried over anhydrous sodium sulfate and evaporated to give a residue which was twice recrystallized from Skellysolve B hexane hydrocarbons and acetoneto give pure 6a-fluoro-17a-hydroxy-l,4-pregnadiene-3,20-dione l7-benzoate.

EXAMPLE 11 'hydroxypregnanc-3,20-dione can be converted with Septomyxa aflinis A. T. C. C. 6737 in a nutrient solution containing assimilable carbon, nitrogen and phosphorus to give 6a-fluoro-17u-hydroxy-1-pregnene-3,20-dione.

All of the 16 In the same manner as shown in Example 5, reacting 6oz fluoro 17a hydroxy 1 pregnene 3,20 dione with acetic anhydride, propionic anhydride, or other acid anhydrides produces the corresponding ester such as the 17-acetate, 17-propionate, or the like of 6a-fiuoro-17ahydroxy-1-preguene-3,20-dione.

EXAMPLE 13 60 fluoro 17a -'hydroxy 1 allopregnene 3,20 dione 17-(fl-cyclopeutylpropionate) A mixture of one gram of Got-fluoro-17a-hydroxy-1-allopregnene-3,20-dione and four milliliters of fl-cyclopentylpropionic acid is heated to eighty degrees centigrade in the presence of one millliliter of trifluoroacetic anhydride for a period of 45 minutes. The mixture is then poured into excess of water, neutralized by the addition one with S-cyclopentylpropionic acid in the presence of trifluoroacetic anhydride yield the corresponding 17-(5- cyclopentylpropionates) of 60a fluoro 17oz hydroxy- 1,4-pregnadiene-3,ZO-dione and 6u-fluoro-17a-hydroxy-1- pregnene-3,20-dione.

It is to be understood that the invention is not to be limited to the exact details. of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of 6 fluoro 17a hydroxy 1 allopregnene 3,20 dione and 6 fluoro 17cc hydroxy 1 allopregnene 3,20- dione 17-acylate wherein the acyl group is of a hydrocarbon 'carboxylic acid containing from one to twelve carbon atoms, inclusive.

2. 6u-fluoro-17a-hydroxy-1-allopregnene-3,20-dione.

3. 6 8-fluoro-17a-hydroxy-1-allopregnene-3,20-dione.

4. 6-fluoro-17a-hydroxy-l-allopregnene-3,20-dione 17- acylates wherein the acyl group is of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive. e

5. Gu-fluoro-17u-hydroxy-1-allopregnene-3,20-dione 17- acetate.

6. A compound selected from the group consisting of .6-fluoro-17u-hydroxy-1,4-pregnadiene-3,20-dione and 6- fluoro 17oz hydroxy 1,4 -.pregnadiene 3,20 dione 17- acylate, wherein the acyl group is of a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive.

7. Got-fluoro-Hot-hydroxy-1,4-pregi1adiene-3,20-dione.

8. 6-fluoro-17a-hydroxy-1,4-pregnadiene-3,20-dione 17- acylate, wherein the acyl group is of a hydrocarbon cariboxylic acid containing from one to twelve carbon atoms,

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6 - FLUORO - 17A - HYDROXY - 1 - ALLOPREGNENE - 3,20 - DIONE AND 6 - FLORO - 17A -HYDROXY - 1 - ALLOPREGNENE - 3,20DIONE 17-ACYLATE WHEREIN THE ACYL GROUP IS OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO TWELVE CARBON ATOMS, INCLUSIVE.
 6. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6-FLUORO-17A-HYDROXY-1,4-PREGNADIENE-3,20-DIONE AND 6FLUORO-17A-HYDROXY -1,4 - PREGNADIENE 3,20 - DIONE 17ACYLATE, WHEREIN THE ACYL GROUP IS OF A HYDROCARBON CARBOXYLIC ACID, CONTAINING FROM ONE TO TWELVE CARBON ATOMS, INCLUSIVE. 